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Valentine, T., 2023. Determining the mechanisms of long-term pain in childhood cancer survivorship. PhD, Nottingham Trent University.
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Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) commonly occurs following platinum-based chemotherapy (e.g. cisplatin). Neonatal exposure to cisplatin results in a delayed but lasting chronic pain, that persists into adulthood, decreasing quality of life. Presently, there are no preventative treatments and no condition-tailored analgesia so current analgesia that are being utilized are either ineffective or result in long-term adverse effects. Furthermore, it may negatively impact on chemotherapy treatment, preventing the administration of chemotherapy at the optimal effective doses and premature discontinuation of therapy. If we are able to understand the mechanisms involved, then we will be able to develop effective preventative and therapeutic strategies. Previous research has demonstrated the involvement of tropomyosin receptor kinase A (TrkA) modulation in causing aberrant nerve fibre growth and development of pain. This thesis investigated the effect of cisplatin treatment and the role of TrkA signalling using both in vitro and in vivo analysis. In vitro models were also explored to identify a modulator of TrkA function.
Firstly, both the in vitro and in vivo models were successfully developed. Isolated dorsal root ganglion (DRG) sensory neurons exposed to varying concentrations of cisplatin for 24 hours displayed a decrease in neurite outgrowth with increasing concentrations of cisplatin, demonstrating neurodegeneration. Similarly, following 24-hours cisplatin treatment, SH-SY5Y cells exhibited a decrease in cell viability with increasing concentrations of cisplatin. Using this cell line model, TrkA expression levels appeared to remain unchanged. However, there was a dose-dependent increase in TrkA phosphorylation following 24-hours cisplatin treatment. In vivo, cisplatin resulted in a persistent but delayed onset of chronic pain in the form of mechanical hypersensitivity, demonstrating peripheral sensory neuronal sensitization. Mechanical hypersensitivity was accompanied by aberrant nerve fibre growth. Administration of cisplatin along with the TrkA inhibitor GW441756, thereby blocking TrkA signalling, ameliorated cisplatin-induced mechanical hypersensitivity and prevented cisplatin-induced aberrant nerve fibre growth. Consequently, the next step was to identify a possible source of TrkA phosphorylation. Notably, cisplatin induced a DNA damage response, evidence by an upregulation in p53 as well as increased phosphorylation of p53 and histone H2A.X, key DNA damage markers.
Novel findings included upregulation of the DNA topoisomerase, TOP2, by cisplatin. Furthermore, in vitro inhibition of TOP2, using doxorubicin, suppressed both cisplatin-induced TrkA phosphorylation in SH-SY5Y cells and cisplatin-induced nociceptor activation in DRG sensory neurons. These results indicate that CIPN is TrkA dependent, which is regulated by TOP2, a modulator of TrkA phosphorylation and nociceptor sensitization. Hence a new analgesic target may have been found in TOP2.
| Item Type: | Thesis | ||||||||||||||||
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| Creators: | Valentine, T. | ||||||||||||||||
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| Date: | April 2023 | ||||||||||||||||
| Rights: | The copyright in this work is held by the author, Tameille Valentine. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the author. | ||||||||||||||||
| Divisions: | Schools > School of Science and Technology | ||||||||||||||||
| Record created by: | Melissa Cornwell | ||||||||||||||||
| Date Added: | 20 Mar 2024 10:24 | ||||||||||||||||
| Last Modified: | 20 Mar 2024 10:24 | ||||||||||||||||
| URI: | https://irep.ntu.ac.uk/id/eprint/51124 |
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